Although acute ischemic stroke is now a treatable condition, thrombolysis, which is the only approved method, is far from perfect because of a short therapeutic window and significant side effect concerns (i.e. intracerebral hemorrhage [ICH]). Even thrombolytic therapy with tissue plasminogen activator (tPA) produces complete resolution of symptoms less than 40% of the time, so there is need for additional forms of therapy. Numerous neuroprotective strategies have been tested in clinical trials, but these methods have not been approved by the FDA for treating ischemic stroke. Transcranial laser therapy (TLT) with low energy infrared irradiation is a form of electromagnetic energy that is able to penetrate into the brain and react with the tissue to produce a series of biochemical reactions. Preliminary data from our laboratory provides evidence that TLT can reduce neurological damage in a rabbit model of embolic stroke. However, the best ways to deliver the energy have not been identified. There are three main objectives of these proposed experiments. First, even though TLT can improve behavioral function, the safety and efficacy profile of TLT has not been evaluated to any substantial extent. Since a wide variety of laser settings can be used to administer TLT, we will systematically alter power density, treatment duration, duty cycle and repeated therapy. We will also determine the effects of TLT on ICH because many ischemic strokes have a hemorrhagic component. Finally, since tPA therapy is the current standard stroke care, it is certain that TLT will be administered in combination with the thrombolytic. We will conduct combination studies to see if tPA and TLT produce beneficial effects when co-administered. Also, since the most feared complication of tPA therapy is ICH, we will investigate whether the TLT alters this relationship. Overall, in this research program, we will identify many important variables of TLT so that the device may be rapidly developed for the treatment of acute ischemic stroke beyond plans already in progress. RELEVANCE: If successful, this program will produce a new form of therapy that will be available to markedly increase the time that physicians will have to treat stroke victims after stroke onset. Since the treatment is probably quite safe, it will be readily adopted by most practitioners. Finally, transcranial laser therapy is in its infancy, and proof of safety and efficacy will markedly accelerate its development for a wide variety of disorders.